By: Sariah Grant PharmD Candidate c/o 2027

Color additives have long played a crucial role in the appearance and appeal of many foods and pharmaceutical products.1 From vibrant candies to easily identifiable medications, synthetic dyes such as Food, Drug and Cosmetics (FD&C) Red Dye No.3, have been used for decades. However, growing concerns over its safety have led to an increase of more stringent regulations.2

On January 15th, 2025, the Food and Drug Administration (FDA) announced its decision to revoke the authorization of FD&C Red Dye No.3 as a color additive in food and ingested drugs. This decision was made in response to a 2022 color additive petition of FD&C Red Dye No.3 2 submitted jointly by Center for Science in the Public Interest (CSPI) and other advocacy groups. Their petition challenged whether the use of Red Dye No.3 complied with the Delaney Clause of the Color Additives Amendment to the FD&C Act.1

Historical Context: The FDA and Regulatory Advancements for FD&C No.3

The FDAis a consumer protection agency in the U.S government that was established in 1906 under the Food and Drugs Act. This legislature addressed and prohibited an increasing number of “adulterated and misbranded” food and drugs.4 As scientific advancements led to a greater understanding of food and drug safety, regulatory measures evolved, leading to the passing of the Federal Food, Drug, and Cosmetic Act of 1938. This law expanded the FDA’s Authority, requiring safety and efficacy testing before drugs could be marketed, mandated accurate labeling, and gained the power to regulate production practices, etc. With growing concerns surrounding color additives, FDA laws became increasingly strict, leading to the addition of the Color Additives Amendment of 1960, which included the Delaney Clause. The Delaney Clause of the Color Additives Amendment was enacted in 1960s, prohibiting the FDA’s use of color additives which have been found to be carcinogenic in either human or animal testing.5

In 1907, FD&C Red Dye No. 3 was originally listed as erythrosine and was temporarily approved for use in food, drugs, and cosmetics in 1960. In 1969, the dye was permanently approved for use in food, drugs, and cosmetics. However, in 1990, the FDA revoked its approval for use in cosmetics and externally applied drugs due to concerns about thyroid cancer in rats. Despite this, its permanent approval for food and ingested drugs remained unchanged.1

The 2022 Petition and FDA’s Regulatory Decision

The 2022 petition submitted jointly by Center for Science in the Public Interest (CSPI) and other advocacy groups, refers to the Delaney Clause to argue their reasoning.

According to the Code of Federal Regulations, Title 21-chapter 1-subchapter A-part 74 (21 CFR 24), a color additive must be revoked if there is sufficient evidence of carcinogenicity in animals, regardless of relevance to humans. Their petition requested that FDA review whether the use of Red Dye No.3 complies with the Delaney Clause of the Color AdditivesAmendment to the FD&C Act.1

After evaluating data submitted in the petition as well as other pertaining data that indicated Red Dye No. 3 induced thyroid tumors in male rats, the FDA made the decision to revoke the authorization of FD&C Red Dye No.3 in ingested foods and drugs. Interestingly, the studies demonstrated “limited relevance to humans.” The tumors are caused by an increase in circulating TSH, which rats are much more sensitive to than humans. There was no evidence that increased TSH even posed a risk of thyroid cancer in humans.Additionally, the exposure levels in humans are relatively low, making the risk of tumors unlikely. However, the FDA’s decision to revoke authorization of Red Dye No.3’s use was upheld due to the legal implications of these findings.1

California’s and the Rest of the World: Bans on Food Additives

California acted ahead of the FDA in its notion to ban Red Dye No.3. On November 17th, 2023, the state amended The California Food Safety Act (AB-418) to not only revoke authorization of Red Dye No.3, but three other additives as well. Surpassing the FDA’s actions, California also prohibited the manufacturing, sale, distribution, and commercial use of food products containing brominated vegetable oil, potassium bromate, and propylparaben.6 Brominated vegetable oil and potassium bromate have been linked to adverse effects on the respiratory and nervous systems, whereas propylparaben may have a detrimental impact on reproductive health.7

The amended law will go into effect in January of 2027, which California’s governor, Gavin Newsom, believes will give companies enough time to adjust their formulations.7 The governor has stood by the law believing that it is “unacceptable that the U.S. is so far behind the rest of the world when it comes to food safety.” 7

Outside of the U.S., other countries have long banned Red Dye No.3 as well as brominated vegetable oil, potassium bromate, and propylparaben, recognizing the potential health risks associated with their consumption. For example, the European Union and Canada have stricter laws regulating the use of these additives in ingested products due to concerns of carcinogenicity, neurotoxicity, and reproductive harm.8

The regulatory gap between the U.S. and other countries is highlighted by the fact that many of the prohibited additives in other countries are still allowed in the U.S. For instance, potassium bromate has been associated with cancer risks in animal studies. In addition, propylparaben, often used as a preservative, has been shown to disrupt endocrine function and pose potential risks to reproductive health.8

As California moves forward with this important legislation, it highlights the growing pressure on U.S. regulators to align with global standards. California’s action is a significant step, setting an example for other states and encouraging the federal government to take stronger action on food safety in the future.8

Implications on the Pharmaceutical Industry

Though a protection to the health of the American people, this ban may have some negative effects to consumers of the pharmaceutical industry. Pharmaceutical companies will have until January 18th 2028 to reformulate their products.2 Though a significant amount of time, this may present a significant challenge to pharmaceutical manufacturers who will need to allocate and test new additives, test stability, determine equivalency, and submit the reformulation for approval by the FDA.9 Additionally, new additives will require a petition requesting approval for the intended use, proving its safety profile before FDA approval.10

Furthermore, supply chain adjustments are necessary as alternative colorants may require sourcing from new suppliers, potentially impacting the cost and availability of raw materials.

Implications on Pharmacies

Due to potential conflicts, pharmacies must prepare for potential drug shortages if manufacturers struggle with reformulations. Pharmacy staff must be on high alert for recalls, ensuring that all products containing Red Dye No. 3 are removed from inventory. In addition, they should scout out pharmaceutical manufacturer’s, vendors, and alternative pharmacies who have an available product. For instances where there is no available manufacture or means to allocate the drug, the pharmacy should work with other disciplines to get the patient on alternative treatment in a timely manner. In all cases, communication is key. The drug shortage information should be disclosed to patients as soon as possible. When usual manufacturers are replaced for different ones, or alternative therapy is decided, the patient should be made aware and counselled on change in appearance of the drug, side effects, and regimen.11

Implications on Public Health

The removal of potentially carcinogenic additives aligns with the ethical responsibility of pharmaceutical companies to prioritize patient safety. However, color additives play a significant role in medication adherence, especially for pediatric, geriatric, and visually impaired patients who rely on color-coded medications to distinguish doses. This presents challenges such as a potential decrease in patient adherence. A study highlights the importance of color in the patient experience and how it may affect the patient’s expectations, behaviors, and adherence. This study found that red, pink, and bright colors stimulated positive emotions in children, making them more receptive to taking the drug.12 These changes cause new questions to arise: will replacement dyes be equally effective in-patient adherence? Could new dyes introduce allergenic or adverse effects? Will the costs of reformulation impact drug pricing? These questions highlight the need for careful consideration of both the safety and practicality in pharmaceutical manufacturing.

Conclusion

The FDA’s revocation of Red Dye No.3 is a major shift in regulatory policy but reinforces the FDA’s critical role in protecting public health. While studies indicate minimal risk to humans, the Delaney Clause left the FDA no choice but to enforce the ban. With examples internationally and even within the country, this ban could spur further regulatory actions on synthetic additives. The transition presents challenges for pharmaceutical manufacturers, who will need to reformulate products. Moving forward, ongoing research, industry adaptation, and regulatory oversight will be key to ensuring consumer safety and the pharmaceutical industry’s compliance.

References:

1. Center for Science in the Public Interest. Color additive petition from Center for Science in the Public Interest et al. requesting to revoke color additive approval of FD&C Red No. 3 in food and ingested drugs. Federal Register. Published January 16, 2025. https://www.federalregister.gov/documents/2025/01/16/2025-00830/color-additive-petition-from-center-for-science-in-the-public-interest-et-al-request-to-revoke-color. Accessed January 31, 2025.
2. U.S. Food and Drug Administration. FDA revokes authorization for the use of FD&C Red No. 3 in food and ingested drugs. Published January 16, 2025. https://www.fda.gov/food/hfp-constituent-updates/fda-revoke-authorization-use-red-no-3-food-and-ingested-drugs. Accessed January 29, 2025.
3. U.S. Food and Drug Administration. FDA history. https://www.fda.gov/about-fda/fda-history. Accessed February 2, 2025.
4. U.S. Food and Drug Administration. Part I: The Food and DrugsAct of 1906 and its enforcement. https://www.fda.gov/about-fda/changes-science-law-and-regulatory-authorities/part-i-1906-food-and-drugs-act-and-its-enforcement. Accessed February 2, 2025.
5. U.S. Food and Drug Administration. Part III: Drugs and foods under the 1938 Act and its amendments. https://www.fda.gov/about-fda/changes-science-law-and-regulatory-authorities/part-iii-drugs-and-foods-under-1938-act-and-its-amendments. Accessed February 2, 2025.
6. California Legislative Information. Bill comparison:AB 418 (2023-2024). https://leginfo.legislature.ca.gov/faces/billCompareClient.xhtml?bill_id=202320240AB4 18&showamends=false. Accessed February 2, 2025.
7. Drexler K. California ban on food additives, including Red Dye No. 3, raises concerns. NPR. Published October 10, 2023. https://www.npr.org/2023/10/10/1204839281/california-ban-food-additives-red-dye-3-propylparaben-candy. Accessed February 2, 2025.
8. Maffini MV, Neltner TG, Vogel S. We are what we eat: Regulatory gaps in the United States that put our health at risk. PLoS Biol. 2017;15(12):e2003578. doi:10.1371/journal.pbio.2003578.
9. U.S. Food and Drug Administration. Changes to an approved NDA or ANDA. https://www.fda.gov/files/drugs/published/Changes-to-an-Approved-NDA-or-ANDA.pdf. Accessed February 2, 2025.
10. U.S. Food and Drug Administration. FD&C Red No. 3. https://www.fda.gov/industry/color-additives/fdc-red-no-3. Accessed February 2, 2025.
11. American Society of Health-System Pharmacists. Managing drug product shortages. https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/managing-drug-product-shortages.ashx. Accessed February 2, 2025.
12. PubMed Central. Impact of FD&C Red No. 3 on health. https://pmc.ncbi.nlm.nih.gov/articles/PMC10384887/. Accessed February 2, 2025.